Defining the Balance between Regeneration and Pathological Ossification in Skeletal Muscle Following Traumatic Injury

Abstract

Heterotopic ossification (HO) is characterized by the formation of bone at atypical sites. This type of ectopic bone formation is most prominent in skeletal muscle, most frequently resulting as a consequence of physical trauma and associated with aberrant tissue regeneration. The condition is debilitating, reducing a patient's range of motion and potentially causing severe pathologies resulting from nerve and vascular compression. Despite efforts to understand the pathological processes governing HO, there remains a lack of consensus regarding the micro-environmental conditions conducive to its formation, and attempting to define the balance between muscle regeneration and pathological ossification remains complex. The development of HO is thought to be related to a complex interplay between factors released both locally and systemically in response to trauma. It develops as skeletal muscle undergoes significant repair and regeneration, and is likely to result from the misdirected differentiation of endogenous or systemically derived progenitors in response to biochemical and/or environmental cues. The process can be sequentially delineated by the presence of inflammation, tissue breakdown, adipogenesis, hypoxia, neo-vasculogenesis, chondrogenesis and ossification. However, exactly how each of these stages contributes to the formation of HO is at present not well understood. Our previous review examined the cellular contribution to HO. Therefore, the principal aim of this review will be to comprehensively outline changes in the local tissue micro-environment following trauma, and identify how these changes can alter the balance between skeletal muscle regeneration and ectopic ossification. An understanding of the mechanisms governing this condition is required for the development and advancement of HO prophylaxis and treatment, and may even hold the key to unlocking novel methods for engineering hard tissues.

Paradoxical sleep deprivation induces differential biological response in rat masticatory muscles: Inflammation, autophagy and myogenesis

“…9 However, there is no consensus regarding how and what inflammatory mediators are involved to this pathobiological phenomenon. 12 Among the biological processes that are able to regulate cell survival or cell death, it is autophagy. 10,11 Apart from these considerations, the inflammatory process can lead to atrophy and, at the same time, tissue regeneration.…”

Recent advances in gene‐enhanced bone tissue engineering

“…In the past, certain clinical cases have demonstrated to physicians that osteoinduction can occur within muscle tissue. After severe soft tissue injuries or implantation of hip prostheses, or in the case of the genetic disease fibrodysplasia ossificans progressiva, the formation of osseous tissue can occur at heterotopic sites. It was not obvious that adipose tissue would represent another promising candidate tissue that is useful as an osteo‐regenerative implant for expedited ex vivo gene therapy.…”

Treatments and Preventative Measures for Trauma‐Induced Heterotopic Ossification: A Review

“…Although small animal models cannot directly mimic the formation of clinically relevant HO, each type of animal study provides the opportunity to better understand the pathophysiology and pathogenesis under unique circumstances. A comprehensive evaluation of the mechanistic pathways of bone growth, healing, and complications that may contribute to HO is beyond the scope of this review but some of the discussions are provided for further investigation 28, 29, 30, 31, 32, 33, 34, 35, 36, 37. With improved understanding, better physical and pharmacological therapeutic protocols can be developed for use in human patients.…”

“…Several animal models have been developed to facilitate a better understanding of the pathogenesis and outcomes of various types of trauma and the occurrence of HO. 25,26 They are used to elucidate several aspects of HO formation, including severity at specific locations, mechanism of injury, and timing of HO formation after injury and have been of great importance to furthering HO research efforts (see Table 1 11,[26][27][28][29][30][31][32][33][34][35][36] ). Outside of specific models aimed directly at studying war-time injuries, such as the Walter-Reed polytrauma and amputation models, few animal models focus directly on the contribution of blunt-force trauma to the formation of HO.…”